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MBC in Press, published online ahead of print June 27, 2007
Mol. Biol. Cell 10.1091/mbc.E07-02-0124

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Submitted on February 14, 2007
Revised on June 11, 2007
Accepted on June 18, 2007

LEKTI Fragments Specifically Inhibit KLK5, KLK7, and KLK14 and Control Desquamation through a pH-dependent Interaction

C. Deraison,*{dagger}{ddagger}{sect} C. Bonnart,*{dagger}{sect} F. Lopez,|| C. Besson,*{dagger} R. Robinson,¶ A. Jayakumar,# F. Wagberg,@ M. Brattsand,** J. P. Hachem,{dagger}{dagger} G. Leonardsson,@ and A. Hovnanian*{dagger}{ddagger}

*Institut National de la Santé et de la Recherche Médicale, U563, Toulouse, F-31300 France; {dagger}Université Toulouse III Paul-Sabatier, Unité Mixte de Recherche-S563, Toulouse, F-31400 France; {ddagger}Centre Hospitalier Universitaire de Toulouse, Hopital Purpan, Departement de Génétique Médicale, Toulouse, F-31000 France; ||Université Toulouse III Paul-Sabatier, Faculté de Médecine Toulouse-Rangueil, Institut Louis Bugnard (IFR31), Toulouse, F-31400 France; Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, United Kingdom; #Department of Head and Neck Surgery, M. D. Anderson Cancer Center, Houston, TX 77030; @Arexis AB/Biovitrum, 413 46 Gothenburg, Sweden; **Department of Public Health and Clinical Medicine, Section for Dermatology and Venereology, Umeå University, SE-901 87 Umeå, Sweden; {dagger}{dagger}Department of Dermatology, Vrije Universiteit Brussels, 1090 Brussels, Belgium

Monitoring Editor: M. Bishr Omary

LEKTI is a 15-domain serine proteinase inhibitor whose defective expression underlies the severe autosomal recessive ichthyosiform skin disease, Netherton syndrome. Here, we show that LEKTI is produced as a precursor rapidly cleaved by furin, generating a variety of single or multi-domain LEKTI fragments secreted in cultured keratinocytes and in the epidermis. The identity of these biological fragments (D1, D5, D6, D8-D11 and D9-D15) was inferred from biochemical analysis, using a panel of LEKTI antibodies. The functional inhibitory capacity of each fragment was tested on a panel of serine proteases. All LEKTI fragments, except D1, showed specific and differential inhibition of human kallikreins 5, 7 and 14. The strongest inhibition was observed with D8-D11, toward KLK5. Kinetics analysis revealed that this interaction is rapid and irreversible, reflecting an extremely tight binding complex. We demonstrated that pH variations govern this interaction, leading to the release of active KLK5 from the complex at acidic pH. These results identify KLK5, a key actor of the desquamation process, as the major target of LEKTI. They disclose a new mechanism of skin homeostasis by which the epidermal pH gradient allows precisely regulated KLK5 activity and corneodesmosomal cleavage in the most superficial layers of the stratum corneum.

{sect}These authors contributed equally to this work.

Address correspondence to: A. Hovnanian (alain.hovnanian{at}toulouse.inserm.fr)




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N. Emami and E. P. Diamandis
Human Kallikrein-related Peptidase 14 (KLK14) Is a New Activator Component of the KLK Proteolytic Cascade: POSSIBLE FUNCTION IN SEMINAL PLASMA AND SKIN
J. Biol. Chem., February 8, 2008; 283(6): 3031 - 3041.
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